Astrocytic responses to high glucose impair barrier formation in cerebral microvessel endothelial cells. Am J Physiol Regul Integr Comp Physiol 2022 Jun 01;322(6):R571-R580
Date
04/13/2022Pubmed ID
35412389Pubmed Central ID
PMC9109795DOI
10.1152/ajpregu.00315.2020Scopus ID
2-s2.0-85130004068 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Hyperglycemic conditions are prodromal to blood-brain barrier (BBB) impairment. The BBB comprises cerebral microvessel endothelial cells (CMECs) that are surrounded by astrocytic foot processes. Astrocytes express high levels of gap junction connexin 43 (Cx43), which play an important role in autocrine and paracrine signaling interactions that mediate gliovascular cross talk through secreted products. One of the key factors of the astrocytic "secretome" is vascular endothelial growth factor (VEGF), a potent angiogenic factor that can disrupt BBB integrity. We hypothesize that high-glucose conditions change the astrocytic expression of Cx43 and increase VEGF secretion leading to impairment of CMEC barrier properties in vitro and in vivo. Using coculture of neonatal rat astrocytes and CMEC, we mimic hyperglycemic conditions using high-glucose (HG) feeding media and show a significant decrease in Cx43 expression and the corresponding increase in secreted VEGF. This result was confirmed by the analyses of Cx43 and VEGF protein levels in the brain cortex samples from the type 2 diabetic rat (T2DN). To further characterize inducible changes in BBB, we measured transendothelial cell electrical resistance (TEER) and tight junction protein levels in cocultured conditioned astrocytes with isolated rat CMEC. The coculture monolayer's integrity and permeability were significantly compromised by HG media exposure, which was indicated by decreased TEER without a change in tight junction protein levels in CMEC. Our study provides insight into gliovascular adaptations to increased glucose levels resulting in impaired cellular cross talk between astrocytes and CMEC, which could be one explanation for cerebral BBB disruption in diabetic conditions.
Author List
Garvin J, Semenikhina M, Liu Q, Rarick K, Isaeva E, Levchenko V, Staruschenko A, Palygin O, Harder D, Cohen SAuthors
Susan Cohen MD Associate Professor in the Pediatrics department at Medical College of WisconsinOlena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Kevin Richard Rarick PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAstrocytes
Blood-Brain Barrier
Cells, Cultured
Coculture Techniques
Connexin 43
Endothelial Cells
Glucose
Microvessels
Rats
Tight Junction Proteins
Vascular Endothelial Growth Factor A
